This is an application for the K08 Mentored Clinical Scientist Research Career Development Award for Dr. Kimberley Evason, a Clinical Instructor at the University of California, San Francisco. Dr. Evason is establishing herself as a young physician-scientist in the research of primary liver cancer (hepatocellular carcinoma, HCC). This K08 award will provide Dr. Evason with the support necessary to accomplish the following career goals: 1) to gain additional expertise in zebrafish biology and histology; 2) to become knowledgeable in cancer signaling pathways; and 3) to develop proficiency in microRNA analysis. To achieve these goals, Dr. Evason has assembled a multi-disciplinary advisory committee comprised of leading zebrafish experts and cancer researchers. HCC is the third leading cause of cancer-related mortality in the world. A major subgroup of HCC is defined by mutations in the gene encoding -catenin, part of the Wnt signaling pathway. Although the main components and targets of the Wnt pathway are well defined, the mechanisms by which alterations in Wnt/ - catenin signaling lead to HCC are not completely understood. There are currently no clinically approved drugs that target the Wnt/ -catenin pathway. Dr. Evason's long-term goal is to elucidate molecular mechanisms by which HCC is initiated and progresses. The overall objective of this application is to identify molecular pathways and chemical compounds that influence -catenin driven HCC formation, using zebrafish as a model organism. The central hypothesis of this application is that activated -catenin promotes tumor formation in fish via activation of specific genes, including myc, epcam, lef1, foxo1a, and iqgap2, and regulation of specific microRNAs. Dr. Evason will achieve the objective of this proposal by pursuing the following specific aims: 1) define ways in which -catenin activation promotes liver tumor formation in zebrafish; 2) identify drugs that inhibit -catenin driven liver growth and tumor formation; and 3) investigate microRNAs that mediate -catenin driven liver tumor formation. Dr. Evason has developed a new model of HCC, in which activated -catenin drives liver growth and tumor formation in zebrafish. In Aim 1, Dr. Evason will test the hypothesis that activated -catenin promotes tumor formation via increased expression of specific genes by performing gain- and loss- of-function experiments. She will use a mouse model to test the hypothesis that -catenin-induced zebrafish liver tumors are capable of malignant cellular behaviors. In Aim 2, Dr. Evason will perform a chemical screen to identify drugs that inhibit -catenin driven liver growth. In Aim 3, Dr. Evason will test the hypothesis that specific microRNAs mediate -catenin driven liver tumor formation by performing microRNA expression analysis. This project is relevant to cancer research and the missions of the NIH and NCI because it has the potential to reveal underlying mechanisms as well as potential therapeutic targets for HCC.